Effect of HIV-1 Infection on Angiopoietin 1 and 2 Levels and Measures of Microvascular and Macrovascular Endothelial Dysfunction

Abstract

Background Individuals infected with HIV have an increased risk of developing cardiovascular disease; yet, the underlying mechanisms remain unknown. Recent evidence has implicated the Tie-2 tyrosine kinase receptor system and its associated ligands ANG1 (angiopoietin 1) and ANG2 (angiopoietin 2) in maintaining vascular homeostasis. In the general population, lower ANG1 levels and higher ANG2 levels are strongly correlated with the development of cardiovascular disease. In this study, we aim to investigate the associations of HIV infection with angiopoietin levels and endothelial dysfunction. Methods and Results In this cross-sectional study, we compared measures of ANG1, ANG2, and endothelial dysfunction using flow-mediated vasodilation of the brachial artery in 39 untreated subjects infected with HIV, 47 treated subjects infected with HIV, and 46 uninfected subjects from the SCOPE (Observational Study of the Consequences of the Protease Inhibitor Era) cohort. Compared with uninfected controls, treated individuals infected with HIV had 53.1% lower mean ANG1 levels (P<0.01) and similar ANG2 levels. On the other hand, untreated individuals infected with HIV had similar ANG1 levels, and 29.2% had higher ANG2 levels (P<0.01) compared with uninfected controls. When compared with individuals with untreated HIV infection, those with treated HIV infection had 56% lower ANG1 levels (P<0.01) and 22% lower ANG2 levels (P<0.01).Both treated and untreated HIV infection were associated with significant impairment in hyperemic velocity, a key measure of microvascular dysfunction (median 61 versus 72 cm/s, P<0.01), compared with uninfected controls (median 73 cm/s). This difference persisted after adjustment for ANG1 and ANG2 levels. Interestingly, when compared with untreated individuals infected with HIV, treated individuals infected with HIV had worse hyperemic velocity (-12.35 cm/s, P=0.05). In contrast, HIV status, ANG1 levels, and ANG2 levels were not associated with macrovascular dysfunction as measured by flow-mediated dilatation and brachial artery diameter, 2 other measures of vascular homeostasis. Conclusions HIV infection affects the balance between levels of ANG1 and ANG2 and may disturb endothelial homeostasis through disruption of vascular homeostasis. Individuals with treated HIV had decreased ANG1 levels and similar ANG2 levels, whereas individuals with untreated HIV had similar ANG1 levels and increased ANG2 levels, suggesting that treatment status may alter the balance between ANG1 and ANG2. HIV also promotes endothelial dysfunction via impairment of microvascular dysfunction, independent of the Tie-2 receptor system; the finding of worse microvascular dysfunction in the setting of treated HIV infection may reflect the impact of viral persistence on the microvasculature or toxicities of specific antiretroviral regimens. Further research to clarify the mechanism of HIV-mediated endothelial dysfunction is necessary to advance treatment of cardiovascular complications of HIV infection.

Keywords: HIV; angiopoietin 1; angiopoietin 2; endothelial dysfunction; endothelial homeostasis.

Figure 1. Association between angiopoietin 2 levels with hyperemic velocity.

Scatter plot of data from which the line of best fit is created. Circles are HIV negative; diamonds are HIV positive, off ARV; squares are HIV positive, on ARV. antiretroviral indicates antiretroval.

Figure 2. HIV infection affects production of angiopoietin 1 and 2, altering endothelial stability, and also directly impairs microvascular function independent of the Tie2 pathway.

A, Treated HIV infection decreases production of angiopoietin1, whereas untreated HIV infection increases production of angiopoietin2. Angiopoietin1 binds to and activates the Tie2 receptor, signaling to inhibit cell apoptosis via protein kinase B‐AKT pathway. AKT inactivates forkhead transcription factor FKHR‐1, which induces angiopoietin 2. Angiopoietin 1 activation of Tie2 also inhibits the nuclear factor‐kB pathway, thus inhibiting inflammation and endothelial permeability. Overall, angiopoietin1 stabilizes the endothelium. On the other hand, angiopoietin2 antagonizes the effects of angiopoietin1. It is released from the endothelial cell Weibel‐Palade bodies in response to cytokines and environmental stressors. Overall, angiopoietin2 destabilizes the endothelium triggering endothelial activation and permeability. B, Our study results suggest that HIV infection—particularly treated HIV infection—also directly impairs microvascular function independent of the Tie2 pathway. ANG indicates angiopoietin; NF‐kB, nuclear factor kappa B; TNF, tumor necrosis factor; and VEGF, vascular endothelial growth factor.